Cholesterol-lowering drugs for treatment of pancreatitis: validation of a clinically significant novel therapeutic target and approach

用于治疗胰腺炎的降胆固醇药物：验证具有临床意义的新型治疗靶点和方法

• 批准号: 10585773
• 负责人: ANNA S. GUKOVSKAYA
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10585773
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; ATP Citrate (pro-S)-Lyase; Acids; Acinar Cell; Acute; Address; Adverse effects; Age; Amylases; Apoptosis; Automobile Driving; Autophagocytosis; Benefits and Risks; Biogenesis; Blood; Categories; Cell Death; Cell model; Cells; Cholelithiasis; Cholesterol; Cholesterol Homeostasis; Chronic; Clinical; Clinical Trials; Critical Pathways; Cytoplasmic Organelle; Disease; Enzymes; Etiology; Exclusion; Exocrine pancreas; FDA approved; Fibrosis; Functional disorder; Future; Healthcare; Healthcare Systems; Heavy Drinking; Hospitalization; Human; Impairment; Incidence; Inflammation; Inflammatory; Intervention; Islets of Langerhans; Lipase; Lysosomal Storage Diseases; Lysosomes; Malignant neoplasm of pancreas; Measures; Medical; Military Personnel; Modeling; Molecular; Mus; Mutation; Necrosis; Oxidoreductase; Pain; Pancreas; Pancreatitis; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Pre-Clinical Model; Prevalence; Preventive; Quality of life; Recycling; Regimen; Risk; Risk Assessment; Risk Factors; Role; Serum; Severities; Severity of illness; Simvastatin; Smoking; Speed; Therapeutic; Tissues; Toxic effect; Treatment Protocols; Trypsinogen; Validation; Veterans; cholesterol biosynthesis; clinically relevant; clinically significant; comparative; cost; drug development; effective therapy; immune cell infiltrate; injured; mouse model; neutrophil; new therapeutic target; novel strategies; pharmacologic; pre-clinical; response; therapeutic target

Pancreatitis is a common, potentially fatal, disease of the exocrine pancreas. There are 2 major forms of pancreatitis: acute (AP), which usually produces an episode of temporary illness, and chronic (CP), associated with severe pain, poor quality of life, and increased risk for the deadliest pancreatic cancer. Pancreatitis is the third most common reason for hospital admissions in those with GI disease and a heavy burden on the U.S. healthcare system Major AP responses include inappropriate/intra-acinar activation of digestive enzymes, increased serum level of amylase, neutrophil-driven inflammation, and acinar cell death. Key pathologic features of CP are loss of acinar tissue, chronic inflammation and fibrosis, ultimately leading to the loss of exocrine and endocrine pancreatic function. It is believed that CP results from repetitive subclinical or clinically evident bouts of AP. Excessive alcohol consumption is a major risk factor for both forms of pancreatitis; other key risk factors are smoking and age. The prevalence of these factors results in high pancreatitis incidence in Veterans as well as in military personnel. The pathogenesis of pancreatitis remains obscure and no effective treatment is available, primarily because we do not understand the underlying molecular and cellular mechanisms. Recent studies indicate that the lysosomal/autophagy pathways – a key catabolic mechanism by which cells eliminate damaged or defective cytoplasmic organelles and recycle their constituents for energy and biogenesis needs – are disrupted in pancreatitis. Our recent study revealed that these pathways are critical for maintaining cholesterol homeostasis in pancreas and their disordering results in acinar cell cholesterol overload. We further showed that the cholesterol-lowering drug simvastatin alleviated experimental pancreatitis. Taken together, these findings suggest that cholesterol metabolism is a clinically relevant modulator of pancreatitis severity. To validate the role of cholesterol dysregulation in driving pancreatitis and establish cholesterol synthesis pathway as a therapeutic target amenable to pharmacologic intervention in pancreatitis, we propose to examine the effects of cholesterol- lowering drugs with different action mechanism, simvastatin and bempedoic acid (BemA), on disease severity in several dissimilar mouse and ex-vivo (cellular) pancreatitis models. These preclinical AP and CP models reflect the spectrum of disease severity and etiologies, such as excessive alcohol consumption, gallstones, and ERCP. Statins came to medical use 30 years ago; BemA, which elicits fewer adverse effects than statins, was recently approved by FDA for lowering cholesterol. The proposed studies will examine the effects of these drugs on pancreatic cholesterol levels and disease severity using various regimens of drug administration in both preventive and therapeutic modes. The Specific Aims will determine the effects of simvastatin and BemA on pancreatitis parameters in preclinical models of AP (Aim 1) and CP (Aim 2) and changes in cholesterol levels in these models (Aim 3A); and compare simvastatin’s effects on ex-vivo pancreatitis responses in mouse versus human acinar cells (Aim 3B). If successful the study will provide information necessary to de-risk future clinical trials to validate the repurposing of simvastatin and/or BemA for pancreatitis treatment, and thus address the unmet clinical needs of Veterans. Comparative analysis of drugs’ effects in several preclinical pancreatitis models will allow us to select the best candidate(s) for clinical trials by excluding treatment regimens with toxic effects in the pancreas, insufficient cholesterol-lowering capacity, and/or little beneficial impact on pancreatitis responses. Repurposing FDA-approved drugs can significantly speed up and lower the cost of these trials. Thus, the proposed detailed study in preclinical models is a necessary prerequisite for clinical trials to assess the risks and benefits of our novel approach to address Veteran healthcare needs.

胰腺炎是一种常见的、可能致命的胰腺外分泌疾病，有两种主要形式。 胰腺炎：急性（AP），通常会产生暂时性疾病，慢性（CP），相关 严重的疼痛、生活质量差以及最致命的胰腺癌的风险增加。 胃肠道疾病患者入院的第三个最常见原因，对美国造成沉重负担 医疗保健系统 主要的 AP 反应包括消化酶的不适当/腺泡内激活， 淀粉酶、中性粒细胞驱动的炎症和腺泡细胞死亡的血清水平升高。 CP 的主要症状是腺泡组织的丧失、慢性炎症和纤维化，最终导致外分泌和 据信，CP 是由反复的亚临床或临床明显发作引起的。 过量饮酒是这两种胰腺炎的主要危险因素； 吸烟和年龄这些因素的普遍存在也导致退伍军人胰腺炎的高发病率。 就像军事人员一样。 胰腺炎的发病机制仍不清楚，并且没有有效的治疗方法，主要是因为 我们不了解潜在的分子和细胞机制。 溶酶体/自噬途径——细胞消除受损或缺陷的关键分解代谢机制 细胞质细胞器并回收其成分以满足能量和生物发生的需要 - 在 我们最近的研究表明，这些途径对于维持胆固醇稳态至关重要。 胰腺中的胆固醇及其紊乱导致腺泡细胞胆固醇超载。 综上所述，降胆固醇药物辛伐他汀可缓解实验性胰腺炎。 表明胆固醇代谢是胰腺炎严重程度的临床相关调节剂以验证其作用。 胆固醇失调在驱动胰腺炎中的作用，并建立胆固醇合成途径作为治疗方法 为了适应胰腺炎的药物干预目标，我们建议检查胆固醇的影响 降低具有不同作用机制的药物辛伐他汀和贝培多酸（BemA）对疾病严重程度的影响 这些临床前 AP 和 CP 模型反映了几种不同的小鼠和离体（细胞）胰腺炎模型。 疾病严重程度和病因的范围，例如过量饮酒、胆结石和 ERCP。 他汀类药物早在 30 年前就进入医疗用途；而 BemA 的不良反应比他汀类药物最近才被使用。 FDA 批准用于降低胆固醇。 拟议的研究将检查这些药物对胰腺胆固醇水平和疾病的影响 在预防和治疗模式中使用不同的药物给药方案来评估严重程度。 目标将确定辛伐他汀和 BemA 对 AP 临床前模型中胰腺炎参数的影响 （目标 1）和 CP（目标 2）以及这些模型中胆固醇水平的变化（目标 3A）并比较辛伐他汀； 对小鼠与人腺泡细胞离体胰腺炎反应的影响（目标 3B）。 如果成功，该研究将提供必要的信息，以降低未来临床试验的风险，以验证 将辛伐他汀和/或 BemA 重新用于胰腺炎治疗，从而解决以下未满足的临床需求 退伍军人对几种临床前胰腺炎模型的药物作用进行比较分析将使我们能够做出选择。 通过排除对胰腺有毒性作用的治疗方案来进行临床试验的最佳候选者， 降低胆固醇的能力不足，和/或对胰腺炎反应几乎没有有益影响。 FDA 批准的药物可以显着加速并降低这些试验的成本，因此，建议详细说明。 临床前模型研究是临床试验评估我们的风险和获益的必要先决条件 满足退伍军人医疗保健需求的新颖方法。